This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-AR-103: Biomarkers: Bench to Bedside for Autoimmune and Inflammatory Skin and Rheumatic Diseases. Some patients with humoral autoimmune disorders who present with hyperactive responses to B cell receptor triggering are postulated to have a defect in the sialic acid acetylesterase (SIAE)/Siglec pathway of peripheral B cell tolerance. Patients with defects in this pathway may be candidates for novel therapies entailing either a "biologic" replacement with human SIAE or the possible use of small molecule inhibitors to an enzyme that functionally opposes the activity of SIAE,. The value and validity of two novel biomarkers in subjects with humoral autoimmune disorders will be investigated. We predict that a subset of patients with systemic lupus erythematosus or with rheumatoid arthritis may exhibit decreased levels of SIAE in the serum or plasma, and/or increased expression of 9-Oacetyl sialic acid on the surface of B cells. Studies are proposed to determine whether these biomarkers correlate with enhanced B cell receptor signaling, or SIAE mutations. If decreased Lyn levels are seen in B cells in some patients it is predicted that enhanced 9-O-acetylation will not be found in individuals with deficient Lyn. A negative correlation with the PTPN22 620W variant is also expected and this will be analyzed. PUBLIC HEALTH RELEVANCE: These studies explore the value of two novel biomarkers in distinguishing patients with lupus and rheumatoid arthritis who may be candidates for a novel approach to therapy.